The advent of implantable blood recirculating devices has provided life saving solutions to patients with severe cardiovascular diseases. Ventricular assist devices (VAD), blood pumps, and prosthetic heart valves (PHV) provide short to long term solutions for such patients. However, blood clots formation and the attendant risk for stroke remains an impediment to these devices. The complex life-long anticoagulant drug regimen they require, which induces vulnerability to hemorrhage and is not a viable therapy for some patients, does not eliminate this risk. Clot formation is potentiated by contact with foreign surfaces and the non-physiologic flow patterns that enhance the hemostatic response by chronically activating platelets. It is now recognized as the salient aspect of blood trauma in devices. We offer to develop state of the art multiscale numerical simulation methodology that will be able to predict and depict flow induced thrombogenicity in devices. Stresses induced by blood flow on platelets can be represented by a continuum mechanics models down to the order of the <m level. However, molecular effects of adhesion- aggregation bonds are on the order of nm. The coupling of such disparate spatiotemporal scales represents a major computational challenge. Our approach couples a macroscopic model that provides information about the flow induced stresses that may activate clotting, transmitted to a micro-to-nanoscale model based on Discrete Particle Dynamics (DPD) approach. This multi-scale model bridges the gap between macroscopic flow and the cellular scales by allowing the platelets to change their shape continuously in response to the mechanical stimuli. The project follows specific aims (1) develop a DPD model of flow induced thrombogenicity; incorporating biochemical and cellular reaction kinetics leading to platelet aggregation, clot formation and embolization. (2)Bridge the gap between macroscopic and molecular scales by incorporating this model into a multiscale model of flow-induced thrombogenicity, translating the stress dynamics to platelet associated biochemical and cellular events. (3) Validate DPD by comparing its predictions to computational fluid dynamics (CFD), and correlating its platelets activation and aggregation predictions to measurements in a blood recirculation loop. (4) Conduct error estimation and parameter sensitivity analysis, and optimize the computational efficiency across the scales in multi-cluster supercomputers. With extended life expectancy, increasing numbers of patients will require CVS devices. The vexing problem of device thrombogenicity calls for innovative approaches that couple biophysical and biochemical transport spanning the spatial and temporal scales. The tools developed in the proposed research are essential for optimizing the next generation of devices in order to reduce mortality rates and the ensuing healthcare costs, and improve patients' quality of life. Recent progress in computational methods and HPC has put such major challenges within our reach. The proposed methodology may stimulate the burgeoning field of multiscale simulations and its application to solving complex clinical problems at the interface of engineering and biology. It represents a paradigm shift in such simulations, advancing our understanding of biotransport processes to a new level that may have a major impact on important problems in biology and medicine. PHS 398/2590 (Rev. 06/09) Page 1 Continuation Format Page PUBLIC HEALTH RELEVANCE: Better understanding of the complex interactions between living tissues and mechanical stimuli, as represented by the vexing problem of flow-induced cardiovascular devices thrombogenicity, calls for innovative multidisciplinary approaches that couple biophysical and biochemical transport phenomena spanning the spatial and temporal scales. In this proposal a multi-scale modeling approach will be developed that will efficiently utilize high performance computing (HPC) resources. The knowledge that will be gained by the proposed research is essential for developing the next generation of devices that will reduce mortality rates, improve patients' quality of life, and reduce the ensuing healthcare costs. The innovative methodology that will be developed may stimulate the burgeoning field of multiscale simulations and its application to solving complex clinical problems at the interface of engineering and biology. It has the potential to advance our understanding of biotransport processes to a new level that will have a major impact on important problems in biology and medicine.